Potassium channels set and modulate the electrical potential of the plasma membrane in multiple cell types. In doing so, they play a major role in a number of physiological processes including neuronal excitability and hormone secretion. In the pancreatic beta cell, one important channel involved in setting the membrane potential is Kir6.2, an ATP-sensitive potassium channel. When levels of glucose are low, the concentration of ATP in the cytoplasm of the insulin secreting beta cell is also low. Under these conditions Kir6.2 channels are open, thereby hyperpolarizing the cell membrane. When glucose levels are high, cytoplasmic ATP concentrations also rise and shut off the current through Kir6.2. This depolarizes the plasma membrane and initiates the voltage-dependent opening of L-type Ca++ channels (Aguilar-Bryan and Bryan, Endocr. Rev. 20:101-135 (1999)).
A number of drugs that act on K+ channels are in use for Type 2 diabetes. The sulphonylurea drugs increase insulin secretion by inhibiting the channel activity of Kir6.2. Sulphonylureas have their activity via interaction with a protein, the sulphoynylurea receptor (SUR1) that associates with Kir6.2 and regulates its activity. Diazoxide is a KATP channel opener that is used clinically for suppressing insulin secretion (ION CHANNELS AND DISEASE (Ashcroft, 2000)). Kir6.2 is found associated with other sulphonylurea receptor proteins (e.g., SUR2A and SUR2B) in other tissues. Mutations in the SUR1 subunit of the KATP channel lead to a syndrome known as Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI) that results in constant depolarization of the beta cell plasma membrane and constitutive secretion of insulin.
Channel forming domains are found in all K+ channels. These elements allow for formation of a K+ permeable channel (Pascual, J. M. et al., Neuron 14:1055-1063 (1995)). The majority of mammalian K+ channels have just one of these features. A subclass of potassium channels has four transmembrane segments domains and two channel forming domains. This subclass forms a single pore by dimerization. There are at least fourteen such channels in the human genome, more than 11 in Drosophila and around 50 in the C. elegans genome. Such channels are often “background” or “leak” channels” because they are open at the resting potential and are likely to be important in setting the resting potential and regulating the excitability of cells.
Diabetes mellitus can be divided into two clinical syndromes, Type 1 and Type 2 diabetes mellitus. Type 1, or insulin-dependent diabetes mellitus (IDDM), is a chronic autoimmune disease characterized by the extensive loss of beta cells in the pancreatic Islets of Langerhans, which produce insulin. As these cells are progressively destroyed, the amount of secreted insulin decreases, eventually leading to hyperglycemia (abnormally high level of glucose in the blood) when the amount of secreted insulin drops below the level required for euglycemia (normal blood glucose level). Although the exact trigger for this immune response is not known, patients with IDDM have high levels of antibodies against pancreatic beta cells. However, not all patients with high levels of these antibodies develop IDDM.
Type 2 diabetes (also referred to as non-insulin dependent diabetes mellitus (NIDDM)) develops when muscle, fat and liver cells fail to respond normally to insulin. This failure to respond (called insulin resistance) may be due to reduced numbers of insulin receptors on these cells, or a dysfunction of signaling pathways within the cells, or both. The beta cells initially compensate for this insulin resistance by increasing their insulin output. Over time, these cells become unable to produce enough insulin to maintain normal glucose levels, indicating progression to Type 2 diabetes.
Type 2 diabetes is brought on by a combination of poorly understood genetic and acquired risk factors—including a high-fat diet, lack of exercise, and aging. Worldwide, Type 2 diabetes has become an epidemic, driven by increases in obesity and a sedentary lifestyle, widespread adoption of western dietary habits, and the general aging of the populations in many countries. In 1985, an estimated 30 million people worldwide had diabetes—by 2000, this figure had increased 5-fold, to an estimated 154 million people. The number of people with diabetes is expected to double between now and 2025, to about 300 million.
Type 2 diabetes is a complex disease characterized by defects in glucose and lipid metabolism. Typically there are perturbations in many metabolic parameters including increases in fasting plasma glucose levels, free fatty acid levels and triglyceride levels, as well as a decrease in the ratio of HDL/LDL. As discussed above, one of the principal underlying causes of diabetes is the inability of beta cells to produce sufficient insulin to maintain glucose levels. Therefore, an important therapeutic goal in the treatment of diabetes is therefore to increase insulin production. The present invention addresses this and other problems.